Spinal muscular atrophy: An update on therapeutic progress

Abstract

Humans have two nearly identical copies of survival motor neuron gene: SMN1 and SMN2. Deletion or mutation of SMN1 combined with the inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA affects 1 in ~6000 live births, a frequency much higher than in several genetic diseases. The major known defect of SMN2 is the predominant exon 7 skipping that leads to production of a truncated protein (SMNΔ7), which is unstable. Therefore, SMA has emerged as a model genetic disorder in which almost the entire disease population could be linked to the aberrant splicing of a single exon (i.e. SMN2 exon 7). Diverse treatment strategies aimed at improving the function of SMN2 have been envisioned. These strategies include, but are not limited to, manipulation of transcription, correction of aberrant splicing and stabilization of mRNA, SMN and SMNΔ7. This review summarizes up to date progress and promise of various in vivo studies reported for the treatment of SMA.

ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice

“…In weight-matched litters (2.99 ± 0.24 g versus 2.94 ± 0.26 g), the ML372-treated cohort displayed substantially greater weight gain compared with vehicle-treated controls (maximal weight of 5.63 g versus 3.87 g) ( Figure 5A). Weight gain in compound-treated littermates has previously been shown to correlate with the potential efficacy of a compound under therapeutic consideration for SMA (11). Moreover, the onset of weight loss was delayed in ML372-treated animals.…”

“…SMA is the consequence of loss of the SMN1 gene, with the number of copies of SMN2 acting as a disease modifier (6,(8)(9)(10). Current investigational approaches to enhance SMN protein levels include increasing SMN2 exon 7 inclusion, increasing overall SMN2 transcript expression, and stabilizing the residual SMN protein in SMA patients (11,12). While the mechanisms that regulate SMN2 splicing have been well documented, less is known about the factors that govern SMN protein stability.…”

Review of Sodium Valproate Clinical and Biochemical Properties

“…The neuroprotective properties of drug have been established in numerous forms of severe central nervous system damages, such as stroke, traumatic brain injury and spinal cord injury. The drug preserves the brain from impairment development via anti-inflammatory, antiapoptotic and neurotrophic effects [19][20][21][22]. Elderly are usually more at risk to the adverse effects of VPA than younger adults.…”

Antisense Mediated Splicing Modulation For Inherited Metabolic Diseases: Challenges for Delivery

“…Regarding clinical trials, ISIS Pharmaceuticals has recently concluded a phase 1 trial in which the safety, tolerability, and pharmacokinetics of escalating doses of the ISIS-SMNRx drug, an ISS-N1-targeting MOE SSO, administered into the spinal fluid as a single injection in patients with SMA (NCT01494701) has been evaluated (Southwell et al, 2012). Moreover, a phase 2 clinical trial has been initiated in patients with infantile-onset spinal muscular atrophy (NCT01839656) (Seo et al, 2013).…”

“…In general, a variety of cis-acting RNA sequences of the SMN2 gene have been targeted by different oligonucleotide chemistries, such as 2¢-OMe, 2¢-O-MOE or morpholino. In particular, the discovery of the intronic splicing silencer N1 (ISS-N1) was an important breakthrough and many reports selected this sequence as the target for SSO treatment (Seo et al, 2013). As previous steps to apply SSO therapy to cure SMA in humans, intrathecal infusion of the SSO was assayed in cynomolgus monkeys, showing this strategy provided therapeutic levels of SSO to all regions of the spinal cord (Passini et al, 2011).…”